title: Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.
abstract: Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors.forename: Hui-Yi
authors.initials: HY
authors.lastname: Shiao
authors.forename: Mohane Selvaraj
authors.initials: MS
authors.lastname: Coumar
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Chang
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Ke
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Chi
authors.forename: Chang-Ying
authors.initials: CY
authors.lastname: Chu
authors.forename: Hsu-Yi
authors.initials: HY
authors.lastname: Sun
authors.forename: Chun-Hwa
authors.initials: CH
authors.lastname: Chen
authors.forename: Wen-Hsing
authors.initials: WH
authors.lastname: Lin
authors.forename: Ka-Shu
authors.initials: KS
authors.lastname: Fung
authors.forename: Po-Chu
authors.initials: PC
authors.lastname: Kuo
authors.forename: Chin-Ting
authors.initials: CT
authors.lastname: Huang
authors.forename: Kai-Yen
authors.initials: KY
authors.lastname: Chang
authors.forename: Cheng-Tai
authors.initials: CT
authors.lastname: Lu
authors.forename: John T A
authors.initials: JT
authors.lastname: Hsu
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Weir-Torn
authors.initials: WT
authors.lastname: Jiaang
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Chao
authors.forename: Hsing-Pang
authors.initials: HP
authors.lastname: Hsieh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000737:chemistry; D045325:HCT116 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010671:Phenylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C586850:1-(4-(2-((6-(4-(2-(dimethylamino)ethoxy)phenyl)furo(2,3-d)pyrimidin-4-yl)amino)ethyl)phenyl)-3-phenylurea; D000970:Antineoplastic Agents; D005663:Furans; D006574:Heterocyclic Compounds, 2-Ring; D008024:Ligands; D008055:Lipids; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D064096:Aurora Kinase A